This invention relates to processes for manufacturing diethylenetriamine-pentaacetic acid ("DTPA") bis(amide) magnetic resonance imaging ("MRI") agents. More specifically, the present invention includes processes for manufacturing [N,N"-Bis[N-(2-methoxyethyl)carbamoylmethyl]diethylenetriamine-N,N', N"-triacetato]-gadolinium(III).
The recently developed technique of MRI encompasses the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. As currently used, the images produced constitute a map of the proton density distribution and/or the relaxation times in organs and tissues. The technique of MRI is advantageously non-invasive as it avoids the use of ionizing radiation.
It is known to administer divalent and trivalent paramagnetic ions in the form of complexes with organic complexing agents as magnetic resonance contrast agents. Such complexes provide the paramagnetic ions in a soluble, non-toxic form, and facilitate their rapid clearance from the body following the imaging procedure. Gries et. al., U.S. Pat. No. 4,647,447, disclose complexes of various paramagnetic ions with conventional aminocarboxylic acid complexing agents. A preferred complex disclosed by Gries et. al. is the complex of gadolinium(III) with diethylenetriamine-pentaacetic acid ("DTPA") represented by the formula: ##STR1##
Paramagnetic ions, such as gadolinium(III), have been found to form strong complexes with ethylenediaminetetraacetic acid ("EDTA") represented by the formula: ##STR2## and with tetraazacyclododecane-N,N', N", N"-tetraacetic acid ("DOTA") represented by the formula: ##STR3## These complexes do not dissociate substantially in physiological aqueous fluids. The gadolinium complex of DTPA has a net charge of -2, whereas the gadolinium complex of EDTA and DOTA has a net charge of -1, and both are generally administered as soluble salts. Typical such salts are sodium and N-methylglucamine. The administration of such salts is attended by certain disadvantages. These salts can raise the in vivo ion concentration and cause localized disturbances in osmolality, which in turn, can lead to edema and other undesirable reactions.
Efforts have been made to design new ionic and neutral paramagnetic metal complexes which avoid or minimize the above mentioned disadvantages. In general, this goal can be achieved by converting one or more of the free carboxylic acid groups of the complexing agent to neutral, non-ionizable groups. For example, S. C. Quay, in U.S. Pat. Nos. 4,687,658 and 4,687,659, discloses alkylester and alkylamide derivatives, respectively, of DTPA complexes. Similarly, published Dean et. al., U.S. Pat. No. 4,826,673 discloses mono--and polyhydroxyalkylamide derivatives of DTPA and their use as complexing agents for paramagnetic ions. It can also be achieved by covalent attachment of organic cations to the complexing agent in such a manner that the sum of positive and negative charges in the resulting metal complex is zero.
R. W. Webber, in U.S. Pat. No. 5,130,120 and Webber et. al. in U.S. patent application Ser. No. 07/377,491, now U.S. Pat. No. 5,137,711, which are incorporated herein by reference, disclose paramagnetic DTPA and EDTA alkoxyalkylamide complexes as magnetic resonance imaging agents. These patents disclose suitable processes for preparing amide derivatives of DTPA and EDTA in the laboratory. However, the disclosed processes include reaction conditions and solvents which are not suitable for manufacturing large quantities of the magnetic resonance imaging agent.
Thus, there is a need in the art for processes for manufacturing diethylenetriamine-pentaacetic acid (DTPA)-bis(amide) magnetic resonance imaging agents.
Such manufacturing processes are disclosed and claimed herein.